PuSH - Publication Server of Helmholtz Zentrum München

Kuczek, D.E.* ; Larsen, A.M.H.* ; Thorseth, M.L.* ; Carretta, M.* ; Kalvisa, A.* ; Siersbæk, M.S.* ; Simões, A.M.C.* ; Roslind, A.* ; Engelholm, L.H.* ; Nößner, E. ; Donia, M.* ; Svane, I.M.* ; Straten, P.T.* ; Grøntved, L.* ; Madsen, D.H.*

Collagen density regulates the activity of tumor-infiltrating T cells.

J. Immunother. Cancer 7:68 (2019)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background: Tumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities.Methods: T cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis.Results: T cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer.Whole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-beta signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells.Conclusions: Our study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.
Altmetric
Additional Metrics?
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords 3d Culture ; Extracellular Matrix ; Immune Modulation ; T Cell Activity ; Tumor Microenvironment; Cancer; Activation; Expression; Migration; Differentiation; Transcription; Mechanisms; Prognosis; Fibrosis; Integrin
ISSN (print) / ISBN 2051-1426
e-ISSN 2051-1426
Quellenangaben Volume: 7, Issue: 1, Pages: , Article Number: 68 Supplement: ,
Publisher BioMed Central
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Immunoanalytics (IMA)